Early-life antibiotics attenuate regulatory T cell generation and increase the severity of murine house dust mite-induced asthma

Abstract

Intermittent exposure to ABX early in life worsened the severity of experimental asthma and reduced pulmonary Tregs; the latter change correlated with decreased microbiome diversity. These data may suggest targets for immunologic or probiotic therapy to counteract the harmful effects of childhood ABX.

Dysbiosis of the gut and lung microbiome has a role in asthma

“…Generally, it is well accepted that changes of the intestinal microbiota, and of their metabolites, has a systemic impact and determines the severity of atopic dermatitis and the susceptibility to asthma [110], especially when occurring in early life [111], up to 1 year after birth [54,112]. This was demonstrated in a mouse model where an antibiotic mix reduced T-regulatory cell (Treg) abundance in the lung and supported house dust mite-specific asthma [100]. Thus, the clinical risk association between antibiotics and allergies can be modeled in mice, but not in recombination-activating gene 1deficient mice, suggesting the antibiotic rather impaired the adaptive immune responses [98].…”

Mouse Microbiota Models: Comparing Germ-Free Mice and Antibiotics Treatment as Tools for Modifying Gut Bacteria

“…Reports of B cell population shifts are varied, with some groups seeing declines in the blood, bone marrow, and tissues after antibiotics treatment, and others noting similar numbers regardless of microbiota depletion (Ochoa-Repáraz et al, 2009 ; Yoshiya et al, 2011 ; Zhang et al, 2015 ; Ekmekciu et al, 2017 ; Josefsdottir et al, 2017 ; Li et al, 2017 ; Thackray et al, 2018 ). Likewise, shifts in antibody responses are inconsistent—in general, total IgG and IgM levels remain similar in different sites analyzed, but secretory and serum IgA levels tend to decrease and serum IgE levels increase after microbiota depletion (Hill et al, 2010 ; Oh et al, 2014 ; Uchiyama et al, 2014 ; Adami et al, 2018 ; Lynn et al, 2018 ; Robak et al, 2018 ). Antigen-specific response to infection or vaccination vary by pathogen, mouse age, and time point after exposure analyzed, but neonates in particular generally produce a less robust response to vaccination after exposure to antibiotics (Ichinohe et al, 2011 ; Lamousé-Smith et al, 2011 ; Abt et al, 2012 ; Diehl et al, 2013 ; Oh et al, 2014 ; Uchiyama et al, 2014 ; Li et al, 2017 ; Lynn et al, 2018 ).…”

“…However, microbiota-depleted mice actually become less susceptible to enteric viral pathogens including murine norovirus and poliovirus (Kuss et al, 2011 ; Uchiyama et al, 2014 ; Baldridge et al, 2015 ), possibly due to direct interactions between viral pathogens and enteric bacteria or due to loss of specific cell types required for viral infection. Antibiotics-treated mice are additionally impaired in their development of tolerance to food antigens (Bashir et al, 2004 ; Kim et al, 2018 ) and are more prone to allergic diseases (Hill et al, 2012 ; Adami et al, 2018 ).…”

Host-microbe cross-talk in the lung microenvironment: implications for understanding and treating chronic lung disease

“…A common finding across inflammatory lung conditions is the outgrowth of the inflammation-associated Proteobacteria phylum [4], and in mice the lung microbiome has been shown to be associated with pulmonary levels of the innate cytokine IL-1α [7]. Additionally, alterations in the microbiome of the gut might influence the immune tone of the lung, which is shown by the development of more severe experimental asthma in germ-free mice [31,47] or mice with disturbed microbiomes due to early-life antibiotic treatment [100,101]. In contrast, the absence of microbiota in germ-free mice or due to antibiotic treatment has recently been shown to protect mice with Kras mutations and p53 loss from lung cancer development [102].…”